The annotated variants are based on the following underlying tools and knowledge resources:
The table below lists all variant-evidence item associations:
The table below lists all variant-evidence item associations:
The table below lists all variant-evidence item associations:
The set of somatic mutations observed in a tumor reflects the varied mutational processes that have been active during its life history, providing insights into the routes taken to carcinogenesis. Exogenous mutagens, such as tobacco smoke and ultraviolet light, and endogenous processes, such as APOBEC enzymatic family functional activity or DNA mismatch repair deficiency, result in characteristic patterns of mutation (i.e. distinct patterns of substitution types in specific seqence contexts). Importantly, recent studies show that mutational signatures could have significant clinical impact in certain tumor types (Dong et al. 2016; Secrier et al. 2016; Kim et al. 2016)
Here, we apply the deconstructSigs package (Rosenthal et al. 2016) to delineate the known mutational signatures in a single tumor. This package compares the patterns of mutations observed in a single tumor with a large set of estimated signatures found across tumor types (Alexandrov, Nik-Zainal, Wedge, Campbell, et al. 2013; Alexandrov, Nik-Zainal, Wedge, Aparicio, et al. 2013).
A total of n = 2475 SNVs were used for the mutational signature analysis of this tumor.
Given an input tumor profile and reference input signatures (i.e. 30 mutational signatures detected by Sanger/COSMIC), deconstructSigs iteratively infers the weighted contributions of each reference signature until an empirically chosen error threshold is reached. In the plots below, the top panel is the tumor mutational profile displaying the fraction of mutations found in each trinucleotide context, the middle panel is the reconstructed mutational profile created by multiplying the calculated weights by the signatures, and the bottom panel is the error between the tumor mutational profile and reconstructed mutational profile. The piechart shows the relative contribution of each signature in the sample.
Alexandrov, Ludmil B, Serena Nik-Zainal, David C Wedge, Samuel A J R Aparicio, Sam Behjati, Andrew Biankin V, Graham R Bignell, et al. 2013. “Signatures of Mutational Processes in Human Cancer.” Nature. Nature Publishing Group.
Alexandrov, Ludmil B, Serena Nik-Zainal, David C Wedge, Peter J Campbell, and Michael R Stratton. 2013. “Deciphering Signatures of Mutational Processes Operative in Human Cancer.” Cell Rep. 3 (1): 246–59.
Dong, Fei, Phani K Davineni, Brooke E Howitt, and Andrew H Beck. 2016. “A BRCA1/2 Mutational Signature and Survival in Ovarian High Grade Serous Carcinoma.” Cancer Epidemiol. Biomarkers Prev., 5~aug.
Kim, Jaegil, Kent W Mouw, Paz Polak, Lior Z Braunstein, Atanas Kamburov, Grace Tiao, David J Kwiatkowski, et al. 2016. “Somatic ERCC2 Mutations Are Associated with a Distinct Genomic Signature in Urothelial Tumors.” Nat. Genet. 48 (6): 600–606.
Rosenthal, Rachel, Nicholas McGranahan, Javier Herrero, Barry S Taylor, and Charles Swanton. 2016. “DeconstructSigs: Delineating Mutational Processes in Single Tumors Distinguishes DNA Repair Deficiencies and Patterns of Carcinoma Evolution.” Genome Biol. 17 (1): 31.
Secrier, Maria, Xiaodun Li, Nadeera de Silva, Matthew D Eldridge, Gianmarco Contino, Jan Bornschein, Shona MacRae, et al. 2016. “Mutational Signatures in Esophageal Adenocarcinoma Define Etiologically Distinct Subgroups with Therapeutic Relevance.” Nat. Genet., 5~sep.